+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling



A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling



Proceedings of the National Academy of Sciences of the United States of America 103(24): 9063-9068



The status of the 66-kDa human estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted protein lacks both transcriptional activation domains of hER-alpha66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to estrogen signaling. We now demonstrate that hER-alpha36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-alpha36 also may transduce estrogen-dependent signaling in other estrogen target tissues.

(PDF emailed within 0-6 h: $19.90)

Accession: 048132767

Download citation: RISBibTeXText

PMID: 16754886

DOI: 10.1073/pnas.0603339103


Related references

A variant of estrogen receptor-a, hER-a36: Transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. Proceedings of the National Academy of Sciences of the United States of America 103(24): 63-8, 2006

Synuclein gamma stimulates membrane-initiated estrogen signaling by chaperoning estrogen receptor (ER)-alpha36, a variant of ER-alpha. American Journal of Pathology 177(2): 964-973, 2011

Estrogen receptor-alpha 36 mediates mitogenic antiestrogen signaling in ER-negative breast cancer cells. Plos One 7(1): E30174, 2012

Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-alpha-dependent and estrogen receptor-alpha-independent mechanisms. Molecular Cancer Therapeutics 7(7): 2096-2108, 2008

Membrane-bound estrogen receptor alpha initiated signaling is dynamin dependent in breast cancer cells. European Journal of Medical Research 23(1): 31, 2018

Placental expression of estrogen receptor beta and its hormone binding variant--comparison with estrogen receptor alpha and a role for estrogen receptors in asymmetric division and differentiation of estrogen-dependent cells. Reproductive Biology and Endocrinology 1: 36, 2003

Role of estrogen receptor alpha in membrane-initiated signaling in neural cells: interaction with IGF-1 receptor. Journal of Steroid Biochemistry and Molecular Biology 114(1-2): 2-7, 2009

The estrogen receptor alpha variant DELTA5 renders full-length receptor less estrogen dependent but elevates basal activity. Proceedings of the American Association for Cancer Research Annual Meeting 44: 445-446, 2003

Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Research 61(15): 5771-5777, 2001

Estrogen-dependent and -independent estrogen receptor-alpha signaling separately regulate male fertility. Endocrinology 150(6): 2898-2905, 2009

Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway. Cellular Immunology 214(1): 12-20, 2002

The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules. Reproductive Biology and Endocrinology 1: 75, 2003

Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent. Biology of Reproduction 67(4): 1268-1277, 2002

Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor-alpha and estrogen receptor-beta. Journal of Biological Chemistry 273(39): 25443-9, 1998

The cell fate determination factor DACH1 is expressed in estrogen receptor-alpha-positive breast cancer and represses estrogen receptor-alpha signaling. Cancer Research 69(14): 5752-5760, 2009